U.S. patent number 4,376,864 [Application Number 06/320,131] was granted by the patent office on 1983-03-15 for cyclic acetals of glutamic acid-.gamma.-semialdehyde, process for their production and use.
This patent grant is currently assigned to Degussa AG. Invention is credited to Karlheinz Drauz, Axel Kleemann, Marc Samson.
United States Patent |
4,376,864 |
Drauz , et al. |
March 15, 1983 |
Cyclic acetals of glutamic acid-.gamma.-semialdehyde, process for
their production and use
Abstract
The invention is directed to cyclic acetals of glutamic
acid-.gamma.-semialdehyde of the formula ##STR1## in which A is an
unsubstituted alkylene group having 2 to 3 carbon atoms or such an
alkylene group substituted by 1 to 2 methyl groups and to a method
of producing a compound of formula (I) by reaction of a compound of
the general formula ##STR2## in which A is as defined above with
hydrogen cyanide or a cyanide ion supplying compound, ammonia or an
ammonium ion supplying compound and carbon dioxide or a carbonate
ion supplying compound and basic hydrolysis of the reaction mixture
obtained and to using the compound of formula (I) to produce
D,L-proline.
Inventors: |
Drauz; Karlheinz (Freigericht,
DE), Kleemann; Axel (Hanau, DE), Samson;
Marc (Hanau, DE) |
Assignee: |
Degussa AG (Frankfurt,
DE)
|
Family
ID: |
6116880 |
Appl.
No.: |
06/320,131 |
Filed: |
November 10, 1981 |
Foreign Application Priority Data
|
|
|
|
|
Nov 15, 1980 [DE] |
|
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3043159 |
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Current U.S.
Class: |
549/373;
549/451 |
Current CPC
Class: |
C07D
207/16 (20130101); C07D 319/06 (20130101); C07D
317/30 (20130101) |
Current International
Class: |
C07D
207/00 (20060101); C07D 207/16 (20060101); C07D
317/30 (20060101); C07D 319/00 (20060101); C07D
317/00 (20060101); C07D 319/06 (20060101); C07D
317/30 (); C07D 319/06 () |
Field of
Search: |
;549/373,451 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Raymond; Richard
Attorney, Agent or Firm: Cushman, Darby & Cushman
Claims
What is claimed is:
1. A cyclic acetal of glutamic acid-.gamma.-semialdehyde of the
formula ##STR9## in which A is an alkylene group with 2 to 3 carbon
atoms or such an alkylene group substituted by 1 to 2 methyl
groups.
Description
SUMMARY OF THE INVENTION
The present invention is directed to cyclic acetals of glutamic
acid-.gamma.-semialdehyde of the formula ##STR3## in which A is an
unsubstituted alkylene group with 2 or 3 carbon atoms or such an
alkylene group substituted by 1 to 2 methyl groups and a process
for its production.
These cyclic acetals of glutamic acid-.gamma.-semialdehyde are
valuable intermediate products for the production of D,L-proline. A
further object of the invention therefore is the use of the
products to produce D,L-proline.
The cyclic acetals of glutamic acid-.gamma.-semialdehyde of general
formula (I) can be produced by a process comprising (a) reacting a
compound of the general formula ##STR4## in which A is as defined
above in aqueous or aqueous-alcoholic solution with hydrogen
cyanide or a cyanide ion supplying compound, ammonia or an ammonium
ion supplying compound and carbon dioxide or a carbonate ion
supplying compound and (b) hydrolyzing the reaction mixture
obtained in step (a) under basic conditions.
The two reaction steps of the process of the invention proceed with
high conversion.
Since the compounds employed of general formula (II) are also
obtainable through hydroformylation of the corresponding
2-vinyl-1,3-dioxolane or 2-vinyl-1,3-dioxane and the latter are
easily obtainable in high yields by acetalization of acrolein with
the corresponding 1,2 glycol or 1,3-glycol, the cyclic acetals of
glutamic acid-.gamma.-semialdehyde of the general formula (I) can
be produced economically. Since the compounds of general formula
(I) then likewise can be changed into D,L-proline easily and with
high yields there is in all opened up a new advantageous,
economical manner starting from acrolein to form D,L-proline.
Examples of compounds employed of general formula (II) are
2-(2'-formylethyl)-1,3-dioxolane,
2-(2'-formylethyl)-4-methyl-1,3-dioxolane,
2-(2'-formylethyl)-4,5-dimethyl-1,3-dioxolane,
2-(2'-formylethyl)-1,3-dioxane,
2-(2'-formylethyl)-4-methyl-1,3-dioxane or
2-(2'formylethyl)-5,5-dimethyl-1,3-dioxane.
The compounds of general formula (II) are reacted in a first
reaction step which is known in itself for the formation of
hydantoins from aldehydes with hydrogen cyanide or a cyanide ion
supplying compound, such as sodium cyanide or potassium cyanide,
with ammonia or an ammonium ion supplying compound, such as
ammonium hydroxide or ammonium chloride, and with carbon dioxide or
a carbonate ion supplying compound, such as sodium or potassium
bicarbonate, sodium or potassium carbonate, or sodium or potassium
carbamate. There can also be employed compounds which
simultaneously supply cyanide and ammonium ions, such as ammonium
cyanide or which simultaneously supply ammonium and carbonate ions,
such as ammonium-carbonate or ammonium carbamate.
The reaction in the first reaction step takes place in water or in
a mixture of water and methanol or ethanol. It can be undertaken in
a wide temperature range. Preferably there is employed a
temperature between 30+ and 90.degree. C., because in this range a
satisfactory reaction speed is attained and the perhaps necessary
superatmospheric pressure does not create an industrial
obstacle.
The amounts of the individual reactants can be varied within a wide
range. Preferably per mole of compound of general formula (II)
there is employed 1 to 1.5 moles of hydrogen cyanide or cyanide ion
supplying compound, 2 to 15 moles of ammonia or an ammonium ion
supplying compound and 1 to 2 moles of carbon dioxide or a
carbonate ion supplying compound. The compounds of general formula
(II) can be reacted simultaneously with all three other reactants.
However, it is likewise also possible to first react it with the
cyanide component and subsequently react simultaneously with the
two other components, or first to react only with the cyanide
component, then react only with the ammonium component and only
after that react with the carbon dioxide or carbonate component. It
is especially advantageous to have the compound of general formula
(II) dissolved in methanol or ethanol and to slowly feed this
solution into an aqueous solution or suspension of the other
reactants at the desired reaction temperature. To achieve high
conversions there is recommended a suitable post reaction time of
for example 5 hours after the time of the feeding in.
Depending on the reaction conditions used the reaction mixture
after carrying out the first reaction step contains besides the
expected hydantoin of the general formula ##STR5## also a more or
less large portion of the .alpha.-N-carbamoyl-carboxylic acid amide
of the general formula ##STR6## wherein in formula (III) and (IV) A
is again as defined above.
However, it is not necessary to separate the two reaction products,
since both of them are transformed in subsequent reaction step (b)
to the cyclic acetals of glutamic acid-.gamma.-semialdehyde.
However, it can be suitable before carrying out the second reaction
step (b) to remove the ammonium salts contained in the crude
reaction mixture of the first reaction step (a), to distill off the
optionally present alcohol and to concentrate the reaction mixture
under reduced pressure.
Them the mixture of compounds of general formula (III) and (IV)
obtained in step (a) is reacted under basic hydrolysis conditions
for forming the .alpha.-aminoacids from the corresponding
substituted hydantoins in a manner known of itself. Preferably
there are used alkali or alkaline earth metal hydroxides or
alkaline metal carbonates in aqueous medium. For example there can
be used with good success NaOH, KOH, Na.sub.2 CO.sub.3, K.sub.2
CO.sub.3, Ca(OH).sub.2 or Ba(OH).sub.2. The reaction temperature
can be varied in a wide range between 20.degree. C. and 200.degree.
C. Preferred are temperatures between 120.degree. C. and
170.degree. C. since in this range satisfactory reaction speeds can
be attained. Especially preferred saponification conditions are
temperatures between 130.degree. and 160.degree. C., reaction times
of 0.5 to 3 hours and a mole ratio of substrate to base of 1:2 to
1:2.5.
After the hydrolysis the reaction mixture is neutralized and the
glutamic acid-.gamma.-semialdehyde-acetal formed of general formula
(I) is isolated. This can occur for example through adsorption on a
strongly acid ion exchanger, e.g. a sulfonated styrene-divinyl
benzene resin.
Since the compounds of general formula (I) in general are readily
soluble in water, however, on occasion it is more advantageous to
employ in the hydrolysis as base an alkaline earth metal hydroxide
or oxide, e.g. calcium hydroxide, barium hydroxide or calcium
oxide, and to undertake the neutralization of the reaction mixture
with a neutralization agent, especially carbon dioxide, which forms
a metal carbonate which is practically insoluble in water. Then by
simple filtration of the precipitated salt there is obtained a
practically pure aqueous solution of the glutamic
acid-.gamma.-semialdehyde-acetal, which can be employed directly
for the production of proline. However, naturally it can also be
concentrated to such an extent, in a given case under reduced
pressure, that the glutamic acid-.gamma.-semialdehyde-acetal is
deposited in crystalline form.
In order to convert the glutamic acid-.gamma.-semialdehyde-acetal
of general formula (I) into D,L-proline, it is reacted at a pH
between 0 and 4, preferably between 0.5 and 3 under the conditions
of a catalytic hydrogenation. The required pH can be adjusted by an
inorganic acid such as hydrochloric acid, sulfuric acid or
phosphoric acid, or by an organic acid, such as oxalic acid, formic
acid, acetic acid, benzene sulfonic acid or p-toluenesulfonic
acid.
As solvent for the hydrogenation treatment there can be used water
or a mixture of water and an organic solvent miscible therewith,
such as methanol, ethanol, isopropyl alcohol, n-butanol,
tetrahydrofurane or dioxane.
As hydrogenation catalyst there are generally preferred the metals
of the 8th side group of the periodic system or suitable compounds
thereof. The metals can be used as such or in known manner applied
on suitable carriers. Especially preferred catalysts are palladium
and platinum and/or their compounds. Examples of suitable catalysts
are finely divided palladium metal, especially as palladium black,
palladium bromide, palladium chloride, palladium iodide, palladium
cyanide, palladium arsenide, palladium nitrate, palladium oxide or
palladium sulfide or complex salts such as tetrachloropalladates,
hexachloropalladates, tetraamine or diamine palladium chlorides as
well as finely divided platinum metal, above all platinum black, or
platinum oxide. Likewise there can be used platinum salts similar
to the palladium salts.
If catalyst carriers are employed, preferred carriers for example
are activated carbon, barium sulfate, silica gel, aluminum oxide or
zeolites.
The hydrogenation catalysts are used suitably in an amount between
0.01 and 50 weight percent, preferably between 0.1 and 10 weight
percent, calculated as active metal and based on the weight of the
glutamic acid-.gamma.-semialdehyde-acetal employed. The
hydrogenation treatment is undertaken continuously or
discontinuously in customary manner at a temperature between
0.degree. and 200.degree. C., preferably between 20.degree. and
100.degree. C., without excess pressure or at a hydrogen pressure
of up to about 100 bar.
After the hydrogenation treatment the catalyst is separated from
the reaction mixture and the D,L-proline formed is isolated in
known manner, e.g. by means of an ion exchanger.
The invention is explained further in the following examples.
Unless otherwise indicated all percentages are by weight.
The process can comprise, consist essentially of or consist of the
stated steps with the recited materials.
EXAMPLE 1
16.3 Grams of 2-(2'-formylethyl)-1,3-dioxolane were dropped into a
suspension of 48 grams of ammonium carbonate, 5.1 grams of
hydrocyanic acid and 110 ml of aqueous ammonia (25%) at 35.degree.
C. in the course of one hour, and the mixture was further stirred
for five hours at 40.degree. C. Subsequently the salts were boiled
out by increasing the temperature (up to 100.degree. C. head
temperature). The remaining aqueous solution was treated with 18.5
grams of calcium hydroxide and heated for 2.5 hours at 150.degree.
C. After cooling to 80.degree. C. the reaction mixture was
neutralized with solid carbon dioxide and the precipitated calcium
carbonate filtered off. The aqueous filtrate was concentrated under
vacuum and the remaining residue recrystallized from water-ethanol
(volume ration 1:9). There were obtained 19.1 grams (87% of theory)
of glutamic acid-.gamma.-semialdehyde-ethylene-acetal
(decomposition point .gtoreq.230.degree. C.).
Elemental analysis: C.sub.7 H.sub.13 NO.sub.4 : Calculated: C,
47.99%; H, 7.48%; N, 7.80%. Found: C, 48.21%; H, 7.55%; N,
7.74%.
.sup.1 H-NMR-Spectrum (D.sub.2 O) ##STR7##
.delta.=1.5-2.2 (m, 4H): H-1', H-2'
.delta.=3.75 (t, 1H): H-3'
.delta.=3.7-4.2 (m, 4H): H-4, H-5
.delta.=4.95 (t, 1H): H-2
EXAMPLE 2
16.3 Grams of 2-(2'-formylethyl)-1,3-dioxolane were dropped into a
suspension of 48 grams of ammonium carbonate, 5.1 grams of
hydrocyanic acid and 110 ml of aqueous ammonia (25%) at 40.degree.
C. in the course of one hour, and the mixture was stirred for a
further five hours at this temperature. Subsequently the salts were
boiled off by increasing the temperature (up to 100.degree. C. head
temperature). The remaining aqueous solution was treated with 42
grams of barium hydroxide and heated for 1 hour at 160.degree. C.
After cooling to 60.degree. C. the reaction mixture was neutralized
with ammonium carbonate and the precipitated barium carbonate was
filtered off. The filtrate was concentrated under vacuum and the
residue recrystallized from water-dioxane. There were obtained 19.7
grams (90% of theory) of glutamic
acid-.gamma.-semialdehyde-ethylene-acetal.
EXAMPLE 3
A solution of 20.7 grams of 2-(2'-formylethyl)-1,3-dioxane in 50 ml
of methanol was dropped into a suspension of 42 grams of ammonium
carbonate, 6 grams of hydrocyanic acid and 120 ml of aqueous
ammonia (25%) at 50.degree. C. in the course of one hour, and the
mixture was stirred for a further three hours at 50.degree. C.
Subsequently the methanol was distilled off up to a head
temperature of 100.degree. C. and the salts were boiled off. The
remaining aqueous solution was treated with 21 grams of calcium
hydroxide and heated for 2.5 hours at 150.degree. C. After cooling
to 80.degree. C. it was neutralized with solid carbon dioxide and
the precipiated calcium carbonate filtered off. The aqueous
filtrate was concentrated under vacuum and the remaining residue
recrystallized from water-ethanol (volume ratio 1:9). There were
obtained 23.3 grams (86% of theory) of glutamic
acid-.gamma.-semialdehydepropylene-1,3-acetal.
Elemental analysis: C.sub.8 H.sub.15 NO.sub.4 : Calculated: C,
50.78%; H, 7.99%; N, 7.40%. Found: C, 51.31%; H, 8.15%; N,
7.35%.
EXAMPLE 4
17.2 Grams of 2-(2'-formylethyl)-5,5-dimethyl-1,3-dioxane dissolved
in 50 ml of methanol was dropped into a suspension of 20 grams
ammonium carbonate, 4.8 ml of hydrocyanic acid and 110 ml of
aqueous ammonia (25%) at 40.degree. C. in the course of one half
hour after which the temperature was held for another 5 hours at
40.degree. C. Subsequently the methanol was distilled off and
through further heating to 100.degree. C. the ammonium salts were
boiled off. The remaining aqueous suspension was treated with 15
grams of calcium hydroxide and heated at 160.degree. C. for 2
hours. After cooling to 80.degree. C. the reaction mixture was
neutralized with solid carbon dioxide and filtered. The filtrate
was concentrated under vacuum and the residue recrystallized from
water-ethanol (volume ratio 1:9). There was obtained 18.7 grams
(86% of theory) of
glutamic-acid-.gamma.-semialdehyde-2,2-dimethylpropylene-1,3-acetal.
Elemental analysis: C.sub.10 H.sub.19 NO.sub.4 : Calculated: C,
55.28%; H, 8.81%; N, 6.45%. Found: C, 55.40%; H, 8.92%; N,
6.40%.
.sup.1 H-NMR-Spectrum (D.sub.2 O) ##STR8##
.delta.=0.75 (s,3H): 5-CH.sub.3
.delta.=1.15 (s,3H): 5-CH.sub.3
.delta.=1.5-2.2 (m,4H): H-1', H-2'
.delta.=3.65 (q, 4H): H-4, H-6
.delta.=3.75 (t,1H): H-3'
.delta.=4.65 (t,1H): H-2
EXAMPLE 5
2.0 Grams of glutamic acid-.gamma.-semialdehydeethylene-acetal were
dissolved in 15 ml of 0.5 N hydrochloric acid at room temperature,
1.0 gram of Pd/C (10% Pd) added and hydrogenated with hydrogen at 1
bar up to the calculated take up amount (250 ml). After separating
the catalyst and concentrating the filtrate there was obtained
80.9% of theory of thin layer chromatographically pure D,L-proline
in the form of its hydrochloride.
EXAMPLE 6
6.0 Grams of glutamic acid-.gamma.-semialdehydeethylene-acetal were
dissolved in 50 ml of 0.25 N hydrochloric acid at room temperature,
2.5 grams of Pd/C (10% Pd) added and hydrogenation carried out at
25.degree. C. in an autoclave at 20 bar H.sub.2 pressure up until
complete conversion.
After working up there was obtained 85.2% of theory of thin layer
chromatographically pure D,L-proline in the form of its
hydrochloride.
EXAMPLE 7
10.0 Grams of glutamic acid-.gamma.-semialdehydeethylene-acetal
were hydrogenated according to Example 6 at 50.degree. C. After
working up there was obtained 83.7% of thin layer
chromatographically pure D,L-proline in the form of its
hydrochloride.
EXAMPLE 8
5.0 Grams of glutamic acid-.gamma.-semialdehydeethylene-acetal were
hydrogenated in 50 ml of 0.1 N sulfuric acid according to Example
5. There was obtained 84.2% of thin layer chromatographically pure
D,L-proline as its sulfate.
EXAMPLE 9
6.0 Grams of glutamic acid-.gamma.-semialdehydeethylene-acetal were
hydrogenated in 50 ml of 90% aqueous formic acid according to
Example 6. The working up yielded 83.0% of free D,L-proline.
EXAMPLE 10
4.0 Grams of glutamic acid-.gamma.-semialdehydeethylene-acetal were
hydrogenated according to Example 5. The hydrochloric acid solution
was concentrated, the residue taken up in 15 ml of water and passed
over a weakly basic ion exchange resin. The proline containing
eluate was concentrated up to dryness. There were obtained 2.23
grams of D,L-proline free from other aminoacids (84.8% of theory)
with melting point 208.degree.-213.degree. C. (decomposition).
EXAMPLE 11
2.0 Grams of glutamic acid-.gamma.-semialdehydeethylene-acetal were
hydrogenated with 0.3 grams of platinum oxide according to Example
6. There was obtained after working up 81% of thin layer
chromatographically pure D,L-proline in the form of its
hydrochloride.
EXAMPLE 12
2.0 Grams of glutamic
acid-.gamma.-semialdehyde-2,2-dimethylpropylene-1,3-acetal were
treated with 1.0 gram of Pd/C (10% Pd) and 15 ml of 0.1 N
hydrochloric acid and hydrogenated in an autoclave at 50 bar and
50.degree. C. until complete conversion. The working up gave 81.5%
of thin layer chromatographically pure D,L-proline in the form of
its hydrochloride.
EXAMPLE 13
18.9 Grams of glutamic
acid-.gamma.-semialdehydepropylene-1,3-acetal were dissolved in 150
ml of 0.1 N hydrochloric acid, 5 grams of Pd/C (5% Pd) added and
hydrogenation carried out with hydrogen at room temperature under
normal pressure until complete reaction occurred. After working up
there were obtained 13.0 grams (86.0%) of D,L-proline
hydrochloride, in thin layer chromatographically pure form. From
this after dehydrohalogenation with a weakly basic ion exchanger
there were obtained 9.78 grams (85.0%) of D,L-proline. Melting
point: 207.degree.-212.degree. C. (decomposition).
The entire disclosure of German priority application No. P 30 43
159.5-42 is hereby incorporated by reference.
* * * * *